Serological response following COVID-19 vaccines in patients living with HIV: a dose–response meta-analysis

To quantify the pooled rate and risk ratio of seroconversion following the uncomplete, complete, or booster dose of COVID-19 vaccines in patients living with HIV. PubMed, Embase and Cochrane library were searched for eligible studies to perform a systematic review and meta-analysis based on PRIMSA guidelines. The pooled rate and risk ratio of seroconversion were assessed using the Freeman-Tukey double arcsine method and Mantel–Haenszel approach, respectively. Random-effects model was preferentially used as the primary approach to pool results across studies. A total of 50 studies involving 7160 patients living with HIV were analyzed. We demonstrated that only 75.0% (56.4% to 89.9%) patients living with HIV achieved a seroconversion after uncomplete vaccination, which improved to 89.3% (84.2% to 93.5%) after complete vaccination, and 98.4% (94.8% to 100%) after booster vaccination. The seroconversion rates were significantly lower compared to controls at all the stages, while the risk ratios for uncomplete, complete, and booster vaccination were 0.87 (0.77 to 0.99), 0.95 (0.92 to 0.98), and 0.97 (0.94 to 0.99), respectively. We concluded that vaccine doses were associated with consistently improved rates and risk ratios of seroconversion in patients living with HIV, highlighting the significance of booster vaccination for patients living with HIV.

Data abstraction and quality assessment. Two investigators (Q.Z and F.Z) independently extracted data based on a predetermined proforma in Microsoft Excel. The following information was collected, including first author, publication year, country, study type, data source, patient number, control number, age, sex, vaccine type, vaccine dose, antiretroviral therapy, COVID-19 history, duration of follow-up, immunoassay, threshold for positive response, antibody titers, and adjustment parameters. We assessed risk of bias using two domainbased tools, including the Risk of Bias in Nonrandomized Studies of Interventions tool for comparative cohort studies, and the Cochrane Risk of Bias 2 tool for randomized controlled studies. For the Risk of Bias in Nonrandomized Studies of Interventions (ROBINS-I) tool 16 , risk of bias judgement per study is noted as low risk when all domains are judged as low risk of bias, moderate risk when one domain is judged as moderate risk of bias, serious risk when one domain is judged as serious risk of bias, or critical risk of bias when one domain is judged as critical risk of bias. For the Risk of Bias in the Cochrane Risk of Bias 2 tool, risk of bias judgement per study is noted as low risk when all domains are judged as low risk of bias, some concerns when one or more domains are judged as some concerns, or high risk when at least one domain is judged as high risk of bias, or when multiple domains are judged as some concerns. Risk of bias for non-comparative cohort studies was regarded as high risk of bias.
Outcomes of interest. The primary outcomes were the seroconversion rate following the uncomplete, complete, or booster dose of COVID-19 vaccines in patients living with HIV. The secondary outcomes were the risk ratios for seroconversion following the uncomplete, complete, or booster dose of COVID-19 vaccines between HIV-infected and non-HIV-infected patients.
Statistical analysis. All the analyses were performed and visualized with R statistic software (3.6.3). The principal summary measures used were pooled rate and risk ratio with 95% confidential interval (CI) of seroconversion following COVID-19 vaccination. χ 2 test and I 2 statistic were performed to evaluate the statistical heterogeneity of the results in the included studies. We considered heterogeneity to be significant when the P value by χ 2 test was < 0.1 or the I 2 statistic was ≥ 50%. The pooled seroconversion rate was assessed using the Freeman-Tukey double arcsine method. The pooled risk ratios were combined by the Mantel-Haenszel approach. Random-effects model was preferentially used as the primary approach to pool results across studies due to underlying clinical heterogeneity (eg, basic characteristics of the patients, COVID-19 history, adjustment for confounders).
The main characteristics and clinical outcomes of the studies for quantitative analysis were summarized in Table 1 and Supplementary Table S2. The included studies were published between 2021 and 2022. Of these studies, 21 were from Europe, 11 from Asia, 9 from North America, 3 from South Africa and 2 from South America. The studies comprised 31 prospective studies and 15 retrospective studies. 19 studies were multicenter and 27 were single-center. The number of patients living with HIV in 18 studies was above 100; the follow-up duration in 15 studies was more than 2 months; only 11 studies had adjusted for potential confounders; the patients living with HIV in 40 studies received antiretroviral therapy; the patients living with HIV in 35 studies were not infected with COVID-19 prior to vaccination. In terms of vaccination type, mRNA vaccines were used in 26 studies; adenovirus vaccines were used in 3 studies; inactivated vaccines were used in 10 studies; and another 7 studies involved two or more vaccines or other types of vaccines. Supplementary Table S2 presents demographic characteristics, immunoassay and threshold for positive response. Supplementary Table S6 shows the detailed risk of bias for each study, and most of studies were regarded as critical or high risk of bias.
Seroconversion rate after uncomplete, complete, and booster vaccination. 16 studies, 42 studies, and 6 studies evaluated the seroconversion rate of patients living with HIV after uncomplete, complete, and booster vaccination, respectively. As shown in Fig. 2a, the seroconversion rate was 75.0% (95% CI 56.4% to 89.9%) after uncomplete vaccination, 89.3% (95% CI 84.2% to 93.5%) after complete vaccination, and 98.4% (95% CI 94.8% to 100%) after booster vaccination. Significant heterogeneity was seen for the pooled seroconversion rate after uncomplete vaccination (I 2 > 50%, P < 0.10) (Supplementary Fig. S1a). The funnel plot and Egger's test (P = 0.47) did not detect the existence of publication bias in these studies ( Supplementary Fig. S1b). The sensitivity analysis performed by using the "leave-one-out" did not markedly change our results ( Supplementary  Fig. S1c). Also, there is significant heterogeneity for the pooled seroconversion rate after complete vaccination (I 2 > 50%, P < 0.10) ( Supplementary Fig. S2). The funnel plot and Egger's test (P < 0.01) suggested the existence of publication bias in these studies ( Supplementary Fig. S3a). After 10 studies were filled, the funnel plot showed the relative symmetry ( Supplementary Fig. S3b), and Egger's test showed no evidence of significant publication bias (P = 0.49). The pooled seroconversion rate turned to be 96.6% (95% CI 92.6% to 99.2%) after complete vaccination. The sensitivity analysis did not significantly change our results ( Supplementary Fig. S3c). As for the pooled seroconversion rate after booster vaccination, moderate heterogeneity was observed (I 2 = 44%, P = 0.11) ( Supplementary Fig. S4a), and the funnel plot showed the relative symmetry ( Supplementary Fig. S4b), and Egger's test showed no evidence of significant publication bias (P = 0.63). The results were stable after sensitivity analysis ( Supplementary Fig. S4c).
Seroconversion compared with controls after uncomplete, complete, and booster vaccination. 10 studies, 31 studies, and 3 studies compared the seroconversion with HIV-negative vaccine counterparts after uncomplete, complete, and booster vaccination. As suggested in Fig. 2b, the risk ratios were 0.87 (95% CI 0.77 to 0.99) after uncomplete vaccination, 0.95 (95% CI 0.92 to 0.98) after complete vaccination, and 0.97 (95% CI 0.94 to 0.99) after booster vaccination. Significant heterogeneity was seen for the pooled risk ratios for seroconversion after uncomplete vaccination (I 2 > 50%, P < 0.10) ( Supplementary Fig. S5a). The funnel plot and Egger's test (P < 0.01) suggested the existence of publication bias in these studies ( Supplementary Fig. S5b). After 5 studies were filled, the funnel plot showed relative symmetry ( Supplementary Fig. S5c), and Egger's test showed no evidence of significant publication bias (P = 0.89). The pooled risk ratios for seroconversion changed to 1.01 (95% CI 0.95 to 1.09) after uncomplete vaccination. The sensitivity analysis performed by using the "leave-one-out" did not markedly change our results except omitting Feng's, Netto's or Wong's study (Supplementary Fig. S5d). Moreover, there is significant heterogeneity for the pooled seroconversion rate after complete vaccination (I 2 > 50%, P < 0.10) ( Supplementary Fig. S6). The funnel plot and Egger's test (P < 0.01) suggested the existence of publication bias in these studies ( Supplementary Fig. S7a). After 13 studies were filled, the funnel plot showed relative symmetry ( Supplementary Fig. S7b), and Egger's test showed no evidence of significant publication bias (P = 0.78). The pooled seroconversion rate turned to be 1.00 (95% CI 0.98 to 1.03) after complete vaccination. The sensitivity analysis did not significantly change our results ( Supplementary Fig. S7c). Besides, there was minimal heterogeneity for seroconversion after booster vaccination (I 2 = 7%, P = 0.34) ( Supplementary  Fig. S8a), and the funnel plot showed relative symmetry ( Supplementary Fig. S8b), and Egger's test showed no evidence of significant publication bias (P = 0.37). The results were stable after sensitivity analysis except omitting Vergori's study ( Supplementary Fig. S8c).

Meta-regression and subgroup analysis for seroconversion compared with controls after complete vaccination.
Univariate meta-regression was further performed to explore the origin of heterogeneity for seroconversion compared with controls after complete vaccination, and results showed that study location and vaccine type were also possible significant moderators (Supplementary Table S8). Subgroup analyses were further performed to evaluate the potential mediators for the pooled seroconversion compared with controls after complete vaccination (Fig. 4, Supplementary Figs. S19-S28). Subgroup analysis according to year of publication demonstrated that the risk ratio was lower in studies published in 2022, compared with studies published in 2021 (0.92 vs. 0.99, P < 0.01). Subgroup analysis on basis of source data suggested that the risk ratio was lower in single-center studies (0.93), compared with multi-center studies (0.99) (P = 0.03). Subgroup analysis stratified by vaccine type showed that the risk ratio was lowest with inactivated vaccine (0.73), compared with mRNA vaccine (0.98), adenovirus vaccine (1.03), or other vaccines (0.92) (P < 0.01). There was no significant heterogeneity among all subgroup comparisons (all P > 0.05) when subgroup analyses were based on study location, study design, sample size, follow-up duration, adjustment, antiretroviral therapy, or COVID-19 history.
Grading the quality of evidence. According to the GRADE approach, the quality of evidence was very low for seroconversion rate after uncomplete or complete vaccination, and the quality of evidence was low for overall seroconversion rate after booster vaccination (Supplementary Table S9a). The quality of evidence was low for seroconversion compared with controls after uncomplete or complete vaccination, and the quality of evidence was moderate for seroconversion compared with controls after booster vaccination (Supplementary  In this meta-analysis, we analyzed 50 studies with a total of 7160 patients living with HIV. We demonstrated that only 75.0% patients living with HIV achieved a seroconversion after uncomplete vaccination, which  In the meta-regression and subgroup analysis, we found that year of publication, study location and vaccine type were possible significant moderators for the pooled rate and risk ratio for seroconversion after complete vaccination. As for year of publication, the seroconversion rate was lower in studies published in 2022, compared www.nature.com/scientificreports/ with studies published in 2021. A possible explanation is that virus variation weakens the effectiveness of the vaccine over time [75][76][77] . Regarding study location, the seroconversion rate was the lowest in South America, followed by Asia, South Africa, North America, and Europe. These location-specific differences were partly because of different vaccine types in these regions 78,79 83 . Our results further validated previous findings, and provided solid evidence through comprehensively analyzing all the published papers. However, the subgroup differences we found highlight the need for high quality studies on these differences, specifically the improvement in the design of studies, greater geographical representation and comparison of vaccine types. Admittedly, our study has several limitations. First, notable heterogeneity was found in some comparisons, which may be attributed to various immunoassay kits, threshold for seroconversion, and immune status at the time of COVID-19 vaccination in patients living with HIV 29,31,84 . However, sensitivity analysis, subgroup analysis and trim-and-fill analysis were used for meta-analysis, suggesting the stability of the results. Second, significant publication bias was observed in some comparisons, partly because most of studies enrolled were on mRNA vaccines, which could cause some bias in the results. Thirdly, here we failed to explore the effect of CD4 T cell absolute counts on the seroconversion of COVID-19 vaccines in HIV patients. This gap was filled by our other study showing that CD4 T cell count is positively correlated with seroconversion among COVID-19 vaccinated patients with HIV 85 . Finally, the rate of seroconversion was pooled after the uncomplete, complete, and booster vaccination. However, seroconversion rate is just an indicator of vaccine immune response and surrogate endpoints for the vaccine's impact on infection rates and the severity of COVID-19 [86][87][88] . Data on clinical efficacy endpoints, such as COVID-19 infection rates in vaccinated patients living with HIV, are still lacking 89 .

Conclusion
Our meta-analysis summarized the pooled seroconversion rate and the pooled risk ratios following the uncomplete, complete, or booster dose of COVID-19 vaccines in patients living with HIV. We concluded that vaccine doses were associated with consistently improved seroconversion rates and risk ratios in patients living with HIV. Our study provides solid evidence that booster vaccination is necessary for patients living with HIV.

Data availability
The data that support the findings of this study are available from the corresponding author upon reasonable request.